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Microsomal prostaglandin E synthase‐1 inhibition in cardiovascular inflammatory disease
Author(s) -
Wang M.,
Song W.L.,
Cheng Y.,
FitzGerald G. A.
Publication year - 2008
Publication title -
journal of internal medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.625
H-Index - 160
eISSN - 1365-2796
pISSN - 0954-6820
DOI - 10.1111/j.1365-2796.2008.01938.x
Subject(s) - medicine , prostacyclin , inflammation , cyclooxygenase , prostaglandin , pharmacology , disease , endocrinology , enzyme , biochemistry , biology
. Prostaglandins (PGs), particularly PGE 2 and prostacyclin (PGI 2 ), are potent mediators of pain and inflammation. Both atherosclerosis and aortic aneurysm exhibit the hallmarks of inflammation. However, randomized trials of inhibitors of PG synthesis – nonsteroidal anti‐inflammatory drugs – reveal that they predispose to cardiovascular risk. This appears to be consequent to inhibition of PGI 2 and PGE 2 formed by cyclooxygenase‐2 (COX‐2). Inhibitors of microsomal PGE synthase‐1 (mPGES‐1) are being developed for relief of pain and interest has focused on their potential impact on the cardiovascular system. Deletion of mPGES‐1 retards atherogenesis and limits aortic aneurysm formation in hyperlipidaemic mice. However, it does not predispose to thrombogenesis and has a limited impact on blood pressure compared to inhibition of COX‐2. This occurs despite the potential of the suppressed PGE 2 in affording cardioprotection via its EP2 and EP4 receptors. However, deletion of mPGES‐1 permits rediversion of the PGH 2 substrate to other PG synthases and augmented formation of PGI 2 and PGD 2 mitigates this effect. However, increased PGI 2 may also attenuate relief of pain. Pain relief seems likely to be a nuanced indication for mPGES‐1 inhibitors, but they have therapeutic potential in syndromes of cardiovascular inflammation, cancer and perhaps in neurodegenerative disease. However, as the products of substrate rediversion vary according to cell type, these drugs may have contrasting impact amongst individuals at varied stages of disease evolution.